Microwave-assisted synthesis and structure–activity relationships of ...

N. M. Nascimento-Júnior et al. / Bioorg. Med. Chem. Lett. 20 (2010) 74–77 75
Figure 1. Design concept of pyrazolo[3,4-b]pyrrolo[3,4-d]pyridine derivatives of series A (1), B (4), and their simplified analogues (5) and (3a).
Scheme 2. Synthesis of the functionalized N-phenyl maleimides (3a–3f) and N-
phenyl azaphthlimide (5).
Alternatively, the use of microwave irradiation under solventfree
conditions has proved to dramatically improve the process
for obtaining new heterocyclic scaffolds exploiting Diels–Alder
reaction as the key-step. 5
Considering this panorama, we described herein the optimization
of the synthetic route to obtain the pyrazolo[3,4-b]pyrrolo[3,4-d]pyridine
derivative (1a) and some previously described
analogues (1b–1d) using microwave-assisted synthesis for the hetero
Diels–Alder step under solvent-free conditions. Thus, we propose
the enlargement of the congeneric series by the
introduction of the isosteric carboxyl group and the electrondonating
methoxy substituent at the W position (series A, Fig. 1).
Moreover, we exploited the developed methodology to synthesize
a new series of simplified heterocyclic analogues (4a–4f) designed
by changing the pyrazole-attached N-phenyl by a N-
methyl group in order to investigate the stereoelectronic and the
lipophilic influences at this position on the sedative profile of pyrazolo[3,4-b]pyrrolo[3,4-d]pyridine
derivatives (Fig. 1).
On the other hand, the exploitation of successive molecular
simplifications on the structure of sedative prototype (1a) led us
to the design of the 3-pyridinylphthalimide (5) and 4-nitrophenylmaleimide
(3a) derivatives, as a result of the suppression
of the pyrazole and the pyridine rings (Fig. 1). The comparative
evaluation of the sedative profile displayed by these heterocyclic
derivatives on the locomotor activity in mice 8 provided a better
understanding of structure–activity relationships associated with
their CNS actions.
Initially, the six functionalized N-phenylmaleimides (3a–3f)
were prepared starting from maleic anhydride (6) and the corresponding
para-substituted anilines (7).
In order to obtain the desired N-phenylmaleimides (3), the different
behavior of this reaction, determined by distinct solubility
and nucleophilicity of the exploited anilines, was taken into consideration.
Thus, only the N-phenylmaleimides (3a–3d) were prepared,
in yields ranging from 63% to 83%, by refluxing a mixture
of (6) and (7) in acetic acid 9 (Scheme 2). On the other hand, the attempt
to prepare the unsubstituted N-phenylmaleimide (3b) and
the 4-carboxyphenylmaleimide (3f) under the same conditions
led to the formation of the carboxy-amide intermediates (8) or
(9), respectively, accompanied by other undesired subproducts.
To avoid this problem, another two-step methodology was selected
to prepare these two N-phenylmaleimides, using ethyl ether as solvent
in the first step, followed by cyclization of the obtained carboxy-amide
derivatives (8) and (9) after treatment with sodium
acetate in acetic anhydride 10 (Scheme 2). Azaphthalimide derivative
(5) was prepared in 23% overall yield (2 steps) through the initial
condensation of 3,4-pyridinedicarboxylic anhydride (10) and
para-nitroaniline (7a) in acetic acid at reflux, followed by cyclization
of the carboxy-amide (11) with AcONa in acetic anhydride
(Scheme 2).
The azadienes (2a) and (2b) were prepared as described previously,
3 in almost quantitative yields through the condensation of
the corresponding pyrazolamines (12) or(13) and DMF dimethylacetal
(14) (Scheme 3). The relative configuration (E) at imine double
bond of azadienes (12) and (13) was determined by 1 H NMR,
through the irradiation of the C-4 attached pyrazole hydrogen
and the evidence of a NOE effect at imine hydrogen (Scheme 3).
This configuration is important to assure the formation of hetero
Diels–Alder adduct presenting antiperiplanar orientation between
the N,N-dimethylamino group and the vicinal hydrogen able to